The overall aim of this research is to identify and characterize four classes of genes involved in multistage carcinogenesis. The first class includes genes associated with susceptibility to tumor promoter-induced neoplastic transformation. The second class includes genes that specify expression of tumor cell phenotype. The third class is tumor suppressor genes, and the fourth, apoptosis-causing genes. Mouse JB6 promotion- resistant (P-), promotion-sensitive (P+), and tumorigenic (Tx) JB6- derived epidermal cell lines have been found to differ in the expression or activity of several susceptibility-related genes described in the accompanying project, Z01CP05383-11 LVC, "Membrane Signal Transduction in Tumor Promotion." Human nasopharyngeal carcinomas (NPCs) from China show a heterozygous expressed mutation in codon 280 of the tumor suppressor gene, p53. New evidence using human Saos-2 (p53 null) and mouse JB6 cell (containing wild-type p53) transfection recipients shows that the novel mutated p53 has oncogenic activity and that it functions dominantly in the presence of wild type p53 to inhibit transcriptional activation and to cause progression toward neoplastic phenotype at two stages. Since a high proportion of human NPCs and tumorigenic mouse JB6 cells express only wild-type p53, we have inquired as to whether events downstream of p53 might be inactivated, thus losing p53-dependent tumor suppressor activity as if a p53 mutation had occurred. WAF1/CIP-1, a gene transcriptionally controlled by p53 that regulates complexes involved in the G1 checkpoint, has been found not to be mutated in NPC or in JB6 tumor cells. A codon 31 polymorphism in WAF1 has been found, however, with distinct patterns of distribution of homozygous and heterozygous statuses in Chinese populations at high or low risk for NPC. A new candidate tumor suppressor gene has been identified by the differential mRNA display technique applied to the mouse JB6 P- to P+ to Tx progression series. This gene, identified as tissue inhibitor of metalloproteinase-3, is expressed in preneoplastic, but not neoplastic (Tx), JB6 cells.